The present invention, in some embodiments thereof, relates to CCL1 molecules and, more particularly, but not exclusively, to the use of same for therapy, such as of inflammatory, autoimmune and transplantation-related diseases.
Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT) leading to significant morbidity and mortality in humans. However, BMT is currently the preferred treatment of a number of malignant and non-malignant diseases, including acute and chronic leukemia, myelomas, lymphomas, aplastic anemia, solid tumors and severe immunodeficiency. Acute and chronic GVHD occurs when transplanted donor-derived T cells recognize and react to histo-incompatible recipient antigens (Ags) and/or cells. Acute GVHD typically occurs within 100 days of transplantation and is a rapidly progressive syndrome characterized by profound wasting, immunosuppression and tissue injury in a number of organs, including the intestines, spleen, skin, liver and lungs.
GVHD is considered to be an inflammatory process, with similarities to inflammatory autoimmunity. Yet, most anti-inflammatory therapies, including those showing success in human inflammatory autoimmunity failed in treating GVHD. For example, targeted neutralization of TNF-α by neutralizing antibodies or soluble receptor to TNF-α successfully suppresses rheumatoid arthritis and several other human inflammatory autoimmune diseases, but not GVHD.
Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell mediated murine autoimmune disease that serves as an experimental model for Multiple Sclerosis (MS). EAE also serves as an experimental model for the development of anti-inflammatory therapeutic strategies for a variety of inflammatory autoimmune diseases and for inhibition of graft rejection. For example, studies showing that inhibition of the CTL-A-CD28 interaction is beneficial for therapy of EAE were extended to a variety of autoimmune diseases including, rheumatoid arthritis, atherosclerosis, myocarditis and also to inhibition of graft rejections.
A potential approach for therapy of inflammatory autoimmune and graft rejection encompasses induction of regulatory T cells (T-regs) that control the function of inflammatory effector T cells. The inflammatory reactivity of effector T cells is tightly regulated by at least two major subsets of CD4+ T cells: those that express the Foxp3+ gene (CD4+ CD25+ Foxp3+ T-reg cells) and those that do not express Foxp3− (CD4+ Foxp3− T cells). FOXp3+ T regs are divided into natural T-regs (n-T-regs) that are polarized during thymic education and induced FOXp3+ T regs (i-T-regs) that are primarily polarized by TGF-β. CD4+ Foxp3− T-regs fall into two major subtypes based on their cytokine profile: those that predominantly produce TGF-β (Th3) and those that mostly secrete IL-10 (Tr1).
Depletion of Foxp3+ CD4+ T cells has been described to result in the development of various inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE) [Alvarado-Sánchez B et al., J Autoimmun. (2006) 27 (2):110-8] and X-linked IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked) [Bennett C L et al., Nat Genet. (2001) 27:20-21] while targeted expression of Foxp3 in Foxp3− cells has been described to induce regulatory T cells that suppress autoimmunity [Hori, S. et al. (2003) Science 299(5609): 1057-1061].
Various approaches for disease treatment via neutralization/antagonism of the C—C chemokine CCL1 (Chemokine ligand 1) have been described, some are summarized infra.
PCT Application No. WO 2003/051921 discloses mutants of CC-chemokines (e.g. CCL1) for the treatment of autoimmune and inflammatory diseases, cancer, or bacterial and viral infections. The CC-chemokine mutants described therein contain a single non-conservative substitution, in a consensus sequence common to a subset of CC-chemokines, and act as an antagonist of the CC-chemokine.
PCT Application No. WO 2003/035105 discloses synthetic chimeric fusion proteins for immuno-therapeutic uses (e.g. treatment of cancer or infectious diseases). The fusion proteins described are bi-functional and comprise two different elements (e.g. cytokines, chemokines, interferons or their respective receptors) linked by a linker peptide.
U.S. Patent Application No. 20090214533 discloses an agent for suppressing regulatory T cell function (or depleting/decreasing T regulatory cell number) in order to increase effector cell responses (e.g. anti-pathogen/tumor). The agents described therein comprise, for example, a fusion protein with a targeting moiety and a toxic moiety, wherein the targeting moiety targets and neutralizes CCL1 activity.
U.S. Patent Application No. 20020111290 discloses methods of diagnosing or evaluating skin injuries or conditions (e.g. lupus erythematosus, atopic dermatitis, inflammatory conditions) by evaluating expression of a chemokine (e.g. CCL1) or a chemokine receptor. U.S. Patent Application No. 20020111290 further discloses methods of treating these conditions by administering an antagonist of the chemokine or chemokine receptor.
Additional art include Mira E et al., J Immunol. (2008) 181:3524-3534, Broady R and Levings M K. Nat Med. (2008) 14: 1155-1156 and Cohen et al., JEM (2002) J Exp Med 196(3): 401-406.